Bottom Line:
The growth factor receptor signaling pathways, particularly the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway can mediate resistance to all forms of endocrine therapy.In contrast, FOXA1 transcription factor is a key determinant of ER function and endocrine response.Intriguingly, a link between hormone resistance induced by the PI3K/Akt/mTOR pathway and the function of FOXA1 has been suggested.

fig01: A schematic diagram of estrogen receptor (ER) signaling. Estrogen (E)-bound ER binds to DNA sequences in the promoter regions of target genes at estrogen response elements (ERE) and works as a transcription factor in the nucleus. The ER can also bind to other transcription factors, such as activator protein-1 (AP-1) and specificity protein-1 (SP-1) at their specific sites on DNA. The ER signaling pathway is also regulated by membrane receptor tyrosine kinases (RTK). These RTK activate signaling pathways such as the PI3K/Akt pathway and the mitogen-activated protein kinase (MAPK) pathway that eventually result in phosphorylation of ER, leading to ER activation.

Mentions:
When estradiol (E2) binds to ER, ER undergoes conformational changes and forms dimers. The ER dimers bind to the estrogen response element sequence within the promoter of target genes and attract a complex of co-factors (co-activators and co-repressors).(4,12) This classic function of ER is its nuclear function, also called its genomic activity (Fig. 1). The E2-ER complexes affect the expression of hundreds of genes involved in proliferation, differentiation, survival, invasion, metastasis and angiogenesis, which are particularly relevant for cancer. The ER can also bind to other transcription factors, such as activator protein-1 and specificity protein-1, at their specific sites on DNA and its transcriptional activity is modulated by this binding.(4) In addition, the ER signaling pathway is also regulated by membrane receptor tyrosine kinases (RTK), including epidermal GFR, HER2 and insulin-like growth factor receptor (IGF1-R).(4) These membrane RTK activate signaling pathways such as the PI3K/Akt/mTOR pathway and the mitogen-activated protein kinase pathway, which eventually result in phosphorylation of ER, thus leading to ER activation (Fig. 1).

fig01: A schematic diagram of estrogen receptor (ER) signaling. Estrogen (E)-bound ER binds to DNA sequences in the promoter regions of target genes at estrogen response elements (ERE) and works as a transcription factor in the nucleus. The ER can also bind to other transcription factors, such as activator protein-1 (AP-1) and specificity protein-1 (SP-1) at their specific sites on DNA. The ER signaling pathway is also regulated by membrane receptor tyrosine kinases (RTK). These RTK activate signaling pathways such as the PI3K/Akt pathway and the mitogen-activated protein kinase (MAPK) pathway that eventually result in phosphorylation of ER, leading to ER activation.

Mentions:
When estradiol (E2) binds to ER, ER undergoes conformational changes and forms dimers. The ER dimers bind to the estrogen response element sequence within the promoter of target genes and attract a complex of co-factors (co-activators and co-repressors).(4,12) This classic function of ER is its nuclear function, also called its genomic activity (Fig. 1). The E2-ER complexes affect the expression of hundreds of genes involved in proliferation, differentiation, survival, invasion, metastasis and angiogenesis, which are particularly relevant for cancer. The ER can also bind to other transcription factors, such as activator protein-1 and specificity protein-1, at their specific sites on DNA and its transcriptional activity is modulated by this binding.(4) In addition, the ER signaling pathway is also regulated by membrane receptor tyrosine kinases (RTK), including epidermal GFR, HER2 and insulin-like growth factor receptor (IGF1-R).(4) These membrane RTK activate signaling pathways such as the PI3K/Akt/mTOR pathway and the mitogen-activated protein kinase pathway, which eventually result in phosphorylation of ER, thus leading to ER activation (Fig. 1).

Bottom Line:
The growth factor receptor signaling pathways, particularly the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway can mediate resistance to all forms of endocrine therapy.In contrast, FOXA1 transcription factor is a key determinant of ER function and endocrine response.Intriguingly, a link between hormone resistance induced by the PI3K/Akt/mTOR pathway and the function of FOXA1 has been suggested.